NHGRI Prioritizes Next Organisms to SequenceFirst group includes chicken, chimpanzee, and the honey bee

Bethesda, Maryland  The National Human Genome Research
Institute has prioritized the next group of organisms to be considered for entry
into the sequencing pipeline as the current efforts with human, mouse and rat
approach completion. The organisms designated as high priority for having their
genome analyzed include chicken, chimpanzee, several species of fungi, a sea
urchin, a microscopic animal commonly used in laboratory studies called Tetrahymena,
and the honey bee. The institute designated two other organisms, the rhesus
macaque and a protozoan, as having a moderate priority for sequencing.

The decision does not specifically launch large-scale sequencing on any of
these organisms. Rather, it creates a pool of candidate organisms on which
the institute-supported sequencing centers can choose to begin working as
capacity becomes available. NHGRI supports large-scale sequencing at the Whitehead
Institute/MIT Center for Genome Research in Cambridge, Mass., the Genome Sequencing
Center at Washington University School of Medicine in St. Louis, Mo., and
the Human Genome Sequencing Center at Baylor College of Medicine in Houston,
Tex. Since the sequencing capacity of these centers is currently committed
to the human, mouse, and rat projects, new genomic sequencing efforts may
not start for some months. Before the centers can start sequencing any of
these other organisms, they must get final permission from NHGRI. The institute
will indicate on its website when a sequencing center has begun sequencing
one of these organisms, as well as the strategy to be employed, and a timetable
for the project.

"We've recently learned surprising things by comparing the mouse to the human
genome," said Francis S. Collins, M.D., Ph.D., director of the National Human
Genome Research Institute, a part of the National Institutes of Health. "The
addition of other genomes helps us find the important parts of the genome
that have been conserved. For example, we already have good matches between
22,500 genes in the mouse with genes identified in human. But that leaves
more than half of the closest matches between the mouse and human genome without
an explanation. These matching regions are highly conserved and must be important,
but we don't yet know what they do."

Acquiring the sequence of various genomes is driving the development of a
new field of biological research called comparative genomics. By comparing
the genomes of different organisms, researchers can understand the structure
and function of the human genome. It also will provide a powerful tool for
studying evolution. Currently, researchers are completing analysis of the
human, mouse and rat genomes. A number of other organisms also have been sequenced,
including a long list of microbes, yeast, fruit fly, roundworm, rice and a
plant called Arabidopsis thaliana.

"The best way to tease out the secrets of the human genome is to compare
it with the other organisms' genomes," said Eric Lander, director of Whitehead
Institute/MIT Center for Genome Research. "By finding the features that evolution
has carefully preserved over hundreds of millions of years, we should be able
to pinpoint the signals that control gene function. This information will,
in turn, translate into practical biomedical knowledge that will spur the
development of better therapies in the future."

An evolutionary perspective should also prove valuable for medical researchers.
"Chimpanzees, for example, do not suffer from some of the diseases that strike
humans, such as malaria and AIDS," said Robert H. Waterston, M.D., Ph.D.,
director of the Washington University School of Medicine sequencing center.
"If we see genetic variants in the human population that we don't see in chimp,
then we'll know that the genetic change occurred after humans evolved from
the non-human primates and may be important for disease susceptibility."

The successful sequencing of the human genome showed that such large projects
could be done for a reasonable cost and that the sequence data are of inestimable
value for biomedical research. As a result, interest in sequencing the genomes
of many other organisms has risen dramatically.

Last summer, NHGRI gathered leading researchers interested in various experimental
organisms to help the institute decide how to select the next ones to be sequenced.
A unique process emerged in which advocates for each experimental model were
encouraged to submit white papers to NHGRI (researchers were also encouraged
to publish these white papers to stimulate discussion in the research community).
The selection process is based on peer review of the white papers by a distinguished
panel, with a focus on the scientific issues to be addressed by new sequence
data. This process allows the broad scientific community, the sequencing centers,
and the NHGRI to participate in a process for setting priorities. New organisms
will be prioritized for genomic sequencing on the basis of specific, well-defined
scientific goals. The specific instructions for preparing a white paper proposal
for sequencing a new organism are posted at
http://www.nhgri.nih.gov/About_NHGRI/Der/org_request/seq_target_genome.html.

"This selection of high-priority organisms will bracket some of the most
important evolutionary transitions," said Richard Gibbs, director of the Baylor
College of Medicine Human Genome Sequencing Center. "The white papers are
the ticket to the 21st century Noah's Ark."

The first set of white papers was submitted in February 2002 and reviewed
by a new NHGRI review group called the Genome Resources and Sequencing Priority
Panel (GRASPP) in March 2002. The review included an assessment of the medical
importance of the proposed project, its importance to basic biological and
evolutionary studies, the size of the research community interested in the
DNA sequence, and the availability of additional research tools that would
allow investigators to take maximal advantage of the new genomic sequence
data. Based on this assessment, proposals were ranked as high, moderate, or
low priority, with no intention of providing rankings within each category.

The panel's recommendations were then reviewed by the National Advisory Council
for Human Genome Research and approved at its May 21, 2002, meeting. Before
sequencing can begin, a center must show that it has capacity to commit to
a new sequencing project. The center's principal investigator will need to
negotiate with NHGRI to select the next organism to sequence from the approved
priority list, and the investigator will prepare a detailed plan, including
a strategy and timetable for sequence. The plan will then be reviewed by the
Sequencing Advisory Panel (SAP); approval by the SAP will be necessary, and
sufficient, for the sequencing project to begin.

The list of organisms that were accorded either high or moderate priority,
and the white papers themselves, will be posted at
http://www.nhgri.nih.gov/DER/Sequencing/proposals.html. The organisms
judged to be of high priority for sequencing and the rationale for the recommendation
are (listed in alphabetical order):

Chicken(Gallus gallus)  The chicken is widely used
as a non-mammalian vertebrate system for investigating several important
biomedical research problems, including the development of the embryo (particularly
the nervous system) and the causes of birth defects. It is the only avian
(bird) system with sufficient research resources currently in place to justify
a genome-sequencing project. The chicken genome sequence is also important
in agriculture; the U.S. Department of Agriculture has expressed interest
in helping to support the project and discussions are underway about possible
co-funding by NHGRI and USDA.

Chimpanzee(Pan troglodytes)  The interest in sequencing
the chimpanzee genome arises from its very close relationship to the human;
there is only 1.2% sequence divergence between the two genomes. It may be
possible to better understand the distinct differences between the two organisms
by studying the two sequences. Comparing the human and chimp genomes, in
particular, may provide insights into human diseases because there are a
number of medical conditions that affect humans but not chimpanzees. Chimpanzees
themselves cannot  and will not  be used in any experimental
studies. A working group will be established to advise NHGRI on such issues
as the appropriate strategy, timetable, and cost. As an additional benefit,
it is hoped that the availability of the chimpanzee genome sequence will
assist in conservation efforts of the species.

Fungi (various species)  The genome sequences of a number
of fungi are of interest because of their medical significance, evolutionary
position, and agricultural and industrial importance. Fungal infections
are an important cause of illness, and learning more about the genomes of
a set of well-chosen fungi should facilitate the development of better treatments
for disease.

Honey Bee(Apis mellifera)  The honey bee is a very
interesting organism from several points of view: 1) its powerful social
instincts and unique behavioral traits make it particularly useful to neurobiologists, 2) it is important to the agricultural community in the U.S. as a pollinator, and 3) it is relevant to human health in several ways, including the potentially serious consequences of bee stings, and as a model for antibiotic resistance,
immunity, allergic reaction, development, mental health, diseases of the
X chromosome and longevity. Because of its agricultural relevance, other
federal agencies, such as USDA, are also interested in collaborating on
the sequencing of the honeybee genome.

Sea Urchin(Strongylocentrotus purpuratus)  The sea
urchin has been an important model system for many years in the study of
basic biology, particularly in developmental biology. The sea urchin occupies
an important evolutionary position with respect to vertebrates and humans.
There is a large body of information about gene expression in the sea urchin
and there are a number of genomic resources available, making the sea urchin
an ideal organism for learning how pathways of genes and proteins regulate
growth and development, with potentially profound implications for understanding
human biology.

Tetrahymena thermophila  Studies of the protozoan
Tetrahymena have made major contributions to genetics and cell biology.
Scientists used this organism to study the structure of telomeres (ends
of chromosomes) and the telomerase enzyme, which has profound importance
in cancer and aging. Tetrahymena research also has shed light on general
phenomena of biology including programmed genome rearrangements.

Two organisms, a protozoan (Oxytricha trifallax) and the rhesus macaque
(Macaca mulatta) were accorded moderate priority for sequencing.

A white paper proposing the sequencing of the cow was deferred. Although
there are persuasive reasons to sequence the cow's genome, white papers for
other organisms from this evolutionary group (dogs, cats and pigs) have yet
to be received, but are expected. The panel felt that it could not prioritize
the cow genome without considering the related genomes at the same time. The
considerable size of genomes in this group (the same size as the human genome),
and budget limitations require careful decision-making. For some of these
organisms, such as the cow and pig, there are potential major agricultural
benefits that will likely lead to a partnership with the U.S. Department of
Agriculture.

"USDA is excited about this new collaboration with NHGRI to sequence the
genomes of important agricultural species," said Joseph Jen, Ph.D., USDA Undersecretary
for Research, Education and Economics. "The peer review process that has placed
the chicken and honey bee in the high priority category is good news to these
industries. As coordinator of the newly established Domestic Animal Genome
Interagency Work Group (IWG), it is USDA's hope to eventually investigate
DNA sequencing of all important livestock species that are an integral part
of our nation's food system. We look forward to NHGRI's contributions as an
important member of the IWG. This is an excellent example of inter-agency
cooperation to leverage the nations infrastructure of high-throughput DNA
sequencing."

As researchers submit additional white papers to NHGRI, more organisms will
be added to the priority groups that can be sequenced by the centers. NHGRI
currently allocates $155 million per year to the support of the sequencing
centers. Many other NIH institutes have provided additional funding in the
past, usually for specific sequencing projects such as the mouse and rat genomes.
Several institutes have already expressed interest in supporting additional
sequencing efforts in the future.